Welcome to the graveyard session. Really delighted that there's so many of you here. I'm David Patterson, University of Oxford, and my co-chair from UCLA, Dr. Peter Hanna. We've got a terrific lineup, actually, the meeting is saving the best for last. Without further ado, Peter, I'll let you kick off with the first introduction. Welcome everyone. It's my pleasure to introduce our first speaker, Dr. Murat Fadim, from Duke University, who will be talking with us about baro-stimulation. Thanks for having me. I'll start. I'll be talking about baro-stimulation therapy. It's a device-based therapy originally developed for hypertension but then moved into the space of heart failure. It has a long history in the space of cardiovascular medicine because it dates back, actually, to the original therapeutic intervention that was done by Braunwald and colleagues, actually, by his first and unfortunate deceased wife, where they introduced that into the space of angina management back in the 1960s. The idea of baro-reflex stimulation, heart failure, comes from the fact that the baro-reflex and, of course, now the crowd is a select, very intelligent crowd that probably knows what the baro-reflex is, but also revised the concept of that's a key reflex that sits in the bilateral carotid bulbs and controls your blood pressure and heart rate function. It's really the main reflex that allows you to stand up without a drop in blood pressure and a dramatic change in heart rate. Now, unfortunately, that baro-reflex, which is primarily parasympathetic, it drives a parasympathetic system. It's a purely afferent reflex that goes through the brain, gets integrated, and then ejects the signals into the periphery. Now, the baro-reflex is downregulated in patients with cardiovascular disease, and heart failure is actually the prime disease state where that reflex is particularly downregulated. Mark Krieger here published the data where you see that in heart failure, here, let's see, I have no mouse, but in black, you have the slope. The response to external changes is simply decreased in patients with heart failure as compared to controls. Now, the worse you are in your disease state, as measured by the NYHA scale, the lower your baro-reflex sensitivity. Well, is that associated with worse outcomes? Yes. The lower your baro-reflex sensitivity, we know it since the 50s and 60s, the worse your related outcome in congestive heart failure. Now, we are indirectly targeting baro-reflex in the autonomic nervous system in the space of heart failure, which is, by the way, the number one cause of hospitalization in the United States. It's the number one cost item to Medicare. In case the EPs in this room wonder why we talk about heart failure, and also the number one driver of UAFib, is that we do inadvertently target the baro-reflex system by giving people what we refer to as guideline-direct medical therapy, or beta-blockers, or Ras inhibitors. All of them are directly and indirectly affecting the autonomic nervous system. But we would argue that in order to suppress the sympathetic tone, which is just the flip side of the baro-reflex. Baro-reflex is a pure parasympathetic input into the brain, not the sympathetic input. Giving somebody a ton of beta-blockers is actually not going to revive the parasympathetic nervous system. We do not have direct, select, parasympathetic driving therapeutic options. One drug is actually mestinone. Good luck giving mestinone to your patients. I give it to my dysautonomic patients, not very well tolerated. But that is actually a parasympathomimetic. So a dedicated technology was developed, again, in the 1960s, where the original experiments in 2000s was picked up by a company called CVRx, unilateral implant, an IPG impulse generator gets implanted below the right or left clavicle, and stimulates all day, every day, at low amounts of energy. What does it do when you actually measure sympathetic activity? The two flip sides. The sympathetic tone that gets indirectly affected has been tested in preclinical models on humans, where it's simply, you turn it on, the sympathetic tone goes up. You measure it with muscle sympathetic nerve activity in the tibia. It goes down and is sustained for six months. So it does what it's intended to do. And the baroreflex sensitivity, sort of the primary action, goes up as you stimulate. Interestingly, it actually ramps up over time, don't know the exact explanation, but it's not an on-off effect immediately. So now, in the space of heart failure with reduced ejection fraction, which is about 50% of the heart failure bucket, that was the first device to be approved for the management of heart failure. The first dedicated device. There was a landmark trial that led to its approval, and there's a BEAT-HF trial that then led to approval in 2019. This was under the breakthrough device designation. When I randomized in an open-label fashion, around 300 patients, half got the device, the other half didn't get the device, and just stayed on medical therapy. At six months, they had to meet, first of all, safety. And because this device is entirely extravascular, unlike your ICDs and pacemakers, the complication rate is just as high as that of a pacemaker, if not lower. It does require a CT surgeon, a vascular surgeon, to actually stitch it on the carotid externally. That's one extra step. You sort of have to refer patients out of your regular silo. But complication-wise, it's a safer device. I truly believe it. I see it in my own practice. The quality of life, six-minute walk distance, and NYHA class were the three individual primary endpoints they had to meet in order to get FDA approval. They did meet it with a little bit help, but the improvement they obtained in all of these individual buckets was actually quite impressive. I mean, 60-millimeter walk distance compared to the control arm, that's a lot. It's clinically significant, statistically significant. So the quality of life improvement by 14 points, anything more than five, is clinically and statistically significant. Also, they measured anti-probiotic PD reduction, that was 25% reduction at the six-month mark. Now, it is an open-label trial, even though randomized, but I think these, quote-unquote, soft endpoints were quite impressive, led to its approval, and that device is now on the market. Now, a phase two post-approval study added additional patients to that BDHF trial and extended the follow-up all the way up to seven years for the first patients enrolled in a cohort. Now, if you look at the primary endpoints, CV mortality and heart failure and morbidity as a heart failure hospitalization, actually, you know, there was absolutely no trend there if you look at the wide confidence interval. Having said that, if you look at every secondary endpoint, which included things like all-cause mortality, LVAD and transplantation, because that's what these patients are at risk for, quality of life, and other statistical plays, such as the wind ratio, where they put the primary endpoint in the wind ratio and added some additional components. Now, there, they looked impressively in favor of the barrier simulation, no matter where you looked. So I don't think that they, you know, flat out failed on, quote-unquote, harder clinical outcomes. So now, the indication for this device is that you need to have an injection fraction of 35 or less, NYHA class 203, symptomatic heart failure. It's hard to convince an asymptomatic patient to, you know, undergo a procedure like that, so that makes sense. And then, anti-pro-BNP less than 1,600. We saw that patients that had an anti-pro-BNP greater than 1,600 didn't derive much benefit. These patients tend to be a little further along. The heart is, quote-unquote, too stretched out. The autonomic tone, at this time point, might be purely compensatory and no longer, actually, the driving force of badness. So now, we have, actually, some post-market approval data. We just recently presented that a THT, commercially implanted device in the first one to two years, and there's not been that many in the first two years after implant, because there was a height of COVID, but it was over 300 devices. We looked at their hospitalization and ER rates prior, here in dark red, versus orange, post-implantation of the device, because we're able to do that through that database, through that commercial database, Premier Healthcare. And as you see, I mean, dramatically, way too good, to be true, reductions in re-hospitalization. The other is, of course, the single arm of real data. I always point out to the company, the reason they do such dramatic changes is because these patients tend to be referred into advanced heart failure centers, get the device, and now plugged into advanced care. That's how data looked, once you plug in, so to say, with the big boys and big girls, to manage your care. In summary, guided direct medical therapy has had huge improvements on heart failure, but unfortunately, the majority of patients remain symptomatic, despite GDMT, in patients with heart failure with reduced ejection fraction. We do have now a number of dedicated heart failure devices for patients with heart failure with reduced ejection fraction. This was one of them. And a BEAT-HF study that I reviewed with you all was the one that led to approval. If you have any questions, we can address them in the next session, or in the next few minutes. Thank you very much. Talk extra fast. So, please, if you have any questions. All right, the floor is open for any questions. Yeah, thank you, Murat. That was really informative. The sort of the final piece of the antiproBNP, the NYH class, et cetera, at one stand, it feels kind of broad. How do you navigate within that, or do you? So, you know, the funny thing is that because the indication is so broad, I mean, everybody seems to, there's no such thing as an asymptomatic patient in a heart failure clinic, I would argue. AntiproBNP list in 1600 is probably two-thirds of the HFREF population, and then LVF less than 35, that meets about a third of your population in heart failure clinics. So, you could apply it to a lot, a lot of patients, and we do very few implants of these in the country yet, at this time point. To some degree, because the indication is so broad, you actually feel not specific enough to intervene. And I always make the point, the one thing that this strategy fails is one mandatory criterion that forces you to implant, LBBB, to do a CRT, right? If you have something that mandates you to go and do this device, they fail to have that specific marker. You know, one thing that I push the company and the community to move forward is that how do we know who's actually sympathetically overdriven or parasympathetically underdriven where you might be a super-responder? Because what I haven't talked about is, what's the response rate? We see about a third of patients have a very good clinical response, have a response on antiproBNP, you know, clearly have improvement of maybe even LVF. A third of patients have just symptomatic benefit, there's no objective criteria. Maybe it's all placebo. And then a third has nothing. So how could we have only super-responders, right? I mean, the same thing comes back to you and EP with CRT devices. But we don't have good prognostic markers for response. Thank you. Very nice talk, Marit. So to that point, what do you see as a potential way to identify the super-responders? Meaning, I mean, doing muscle sympathetic nerve activity is impossible, but people have played with skin sympathetic nerve activity and a few other things. Is there anything you see as a potential reasonable screening tool that we could use? Well, so, I mean, I think hardware variability. Think of watches that already technically could measure this basic, which goes parasympathetic tone is actually a key driver of hardware variability. I think the company missed out on the big opportunity to collect on that data. Believe it or not, they never collected that data in hundreds of patients. So as part of registries, they could do that, but now will never be a randomized sample to tell them whether it's true response or not. But I think hardware variability would be the easiest way. So now the other thing is, how do you measure barrier reflex sensitivity? You actually can measure barrier reflex sensitivity for those that don't know how it's measured. It's funny. I trained at Vanderbilt. We actually had the device for that. You put a dog collar on patients. It's a massive piece of equipment, and it supplies a vacuum on your neck. So if you have negative pressure, the body thinks your blood pressure drops and over-activates. So you then look at blood pressure and heart rate responses in response to vacuum applied to your neck. As opposed to, of course, massage and see a drop in your blood pressure, which is a little bit more dangerous. That's why we don't do that. But that's how Mark Krieger measured the dose response to negative pressure. So you could actually do that as well. But find a simpler version of that, boom. And then we have barrier reflex sensitivity measurement technologies that we do for tilt table tests, where they just measure your blood pressure variability with time. And then deduce through their proprietary software what your barrier reflex sensitivity is. I'm just not familiar what actually goes into it. But there are ways to look at this. Have you looked at more classical pharmacological testing, like phenylephrine techniques, sodium nitroprusside, pushing the pressure up and down? I mean, no. I have not. And there's nothing that I know specifically to this device either. Yeah, because that's kind of more the gold standard measure, isn't it? Was there any improvement in their dyspneic rating? Were they breathless? Yes. Okay, so was there an improvement in breathlessness scores and things like that? Yes, they measure NYHA scale, which is physician assessed, and then Minnesota living with heart failure, which is patient assessed. Yes. Okay, good. Yep. Great. Thank you, Mark. Thank you very much. Great. So I was going to kind of switch the order a little bit, because Dr. Efimov's got to get his Learjet back to Chicago. So great pleasure to introduce Dr. Igor Efimov from Northwestern, and he's going to be talking about biodegradable electronics. Igor? Do I need to escape first? I'm trying to push here. You need to push it here. Not on this screen. Well, thank you very much for this invitation to this session. I'm really delighted to show today new technology, which I think will be useful in neuromodulation, but mostly I will be talking about cardiac applications. So we just published two weeks ago this little pacemaker, which is the size of less than a grain of rice, as you can see here from this picture, and also it's bioresorbable, if necessary. So you can make it, it's a built-in concept of transient electronics. So I'm part of this Query-Simpson Institute for Bioelectronics headed by real material science pioneer, Dr. John Rogers at Northwestern University, where we are working on developing numerous platforms for bioelectronics, including soft skin-like electronics which conforms to different organs, including heart, muscle, et cetera, brain, cellular-scale injectable electronics, millimeter-scale wireless wearables, which can do various types of sensing, including biomarkers, for example, inflammation biomarkers, transient electronics, which is made of bioresorbable materials, three-dimensional electronic networks, which can, for example, seamlessly interface with organoids or engineered heart tissues or different other organs. And then also, there is already actually traded on NASDAQ, this company which sells soft skin-interface microfluidic systems, for example, biomarkers from the sweat. So we started many years ago with John by building this skin-like device. It's already more than 10 years ago, which really laid foundation for various applications. Currently, we're working on spinal cord sensing and stimulation. This is unpublished work where we have two different versions of that. One is this is a fully integrated, fully implantable device, which has RF communication, of course, but also microprocessor and can do closed-loop applications for neural stimulation and cardiac sensing. This is example of engineered heart tissue, bioelectronics, which can be, again, interfaced and integrated with the tissue, which can be transplanted later into patient. But today, I will talk about stimulation. And I will start with a biology lesson. So you should try to remember who was the first to discover stimulation. And it's not Galvani. It's actually Svamerdam. In 1668, he did this experiment where he stimulated nerve attached to the frog muscle, and he pinched this nerve by essentially what we now call bimetallic pair of silver and copper. And he thought at that time, because electricity was not yet known, that this was mechanical stimulation. But of course, Galvani later took zinc and copper bimetallic pair, and he stimulated it more successfully 100 years ago, and that's why we know now it's a Galvanic stimulation. So we will do basically the same. So yesterday, actually, Tim Lasky shared with us history how when Walt Lilleheim at University of Minnesota did the first open-heart surgery in children, he found that you needed to stimulate the heart because of AV block. And Earl Bakken, who was an engineer working for University of Minnesota at the time, designed this first stimulator shown right here. And yesterday, you could actually see a replica of the original stimulator. An idea was to attach a wire to the patient's heart, and then you attach it to externalized stimulator. This is history of Medtronic devices. So this is history, but of course, currently, we have implantable and temporary stimulators. These are some examples of that. In our work, we pursued an idea to make it bioresorbable, basically temporary, so you can fully implant it, it will resorb when you don't need it anymore. And we have two versions of that. One is without power source, which is based on antenna by which you can transfer by inductive power transfer energy from external device. And this one I will show more about today. This is a device which does have a source, the same way like what Galvani did. It's a biometallic pair, which produces electricity, but you trigger it by optical means. So first, we designed device, and it shows concept is here. So it has antenna, which you can interface with external antenna, like you charge your cell phone, for example. And then it has literally two diodes, which will rectify the AC current, and then you can apply it to either to platinum electrodes for electrical stimulation or to the microLED for optogenetic stimulation. So we developed procedure for animals. And then next step was to design bioresorbable device, which was essentially the same based on physical principles, but made of these materials, which are bioresorbable. Just to give you an example, magnesium actually is a good conductor, but it's bioresorbable in small quantities, it's safe. You have also silicon, which is a diode material. Silicon, by the way, it's also bioresorbable. Also materials for interconnects, insulating materials, et cetera. So if you drop this device in the ceiling, 40 days later, it will completely dissolve. And if you put it in a mouse and put coil around the cage of the mouse, you can control this device 24-7. It's safe, so we published it a few years ago, so there are no evidence of any inflammation. Body weight of animal is normal, ejection fraction doesn't change. There's a little bit of fibrosis at the site of attachment, but otherwise, it's a very safe device. So now, in this new work, we scaled it down even more. So this is how device looks like, and if you look at the physics of that, it's very simple. Like I said already, as galvanic, we use two materials, two metals, which form a galvanic element. In this case, it's magnesium and molybdenum trioxide. These two metals produce about 1.2 volt of electricity if you make a battery out of it. But they are connected with a photodiode, phototransistor, which normally is disconnected. And then everything is encapsulated in this transparent material, which prevents penetration of biofluids inside the battery. The only point of contact is essentially here below, where you put it on the tissue, and you literally connect to the tissue with your anode and cathode. And then when you shine light on it, you connect the circuit and you can stimulate. Because it's so small, we can deliver this small device in a number of ways. Of course, you can do it with a catheter, like normal, leadless pacemaker is done. You can inject it into the heart. We're also working on a small robotic system, which can navigate inside the blood vessels and can deliver it to, for example, multi-site pacing. So this is an example of chemistry which is involved in this device. You can read it. So it's bioresorbable, as you can see here. So basically, about the same 40 days. Here it was accelerated aging at 95 degrees C. But with normal temperature, it takes about 40 days to dissolve this material. So if you shine light on the device shown here, there's pulses of light. So the device generates current, as shown here. You can control precisely the waveform for stimulation. There is dependence of light intensity versus intensity of current. So essentially, at some intensity, it goes to a plateau. So you can very precisely control your voltage. So we tested it first on explanted pig and human heart, so you can achieve very safe pacing for multiple locations. So then, how do you actually control it? To control it, you need to wear a device on the chest of the patient or animal, which will have sensing of electrocardiogram. And then, it will have a light-emitting diode to actually stimulate the phototransistor to produce electrical pulses. First, we tested it in an animal, a small animal test. And basically, the device was either attached surgically with a suture, or we also developed bioadhesive, which is a hydrogel-based, very conductive bioadhesive, very safe. It's also bioresorbable. So you place it on the heart surgically or inject it. And then, you close the animals, and you put this device on the back of the animal. So you have two electrodes for electrocardiogram, light-emitting diode right here, microprocessor. Of course, we have also RF communication with external device, integrating it to the network. So we programmed, in this case, rat that bradycardia is below 220 beats per minute. So device detected 210 beats per minute and commenced electrical stimulation. You can see it now pacing at 240 beats per minute. So this device, you can appreciate the size of it. This is rat. So this is a CT. As you can see, you will see here, device will be left when we strip all the other tissues right here. Or in this projection, it's a very small device. So we can inject it both in the heart, or we also did already experiments in the spinal cord. So we're developing horseshoe-shaped device, which can be pinched on the nerve or on dorsal root ganglia. Oops, yeah, trying to get to the next slide. So it's also MRI compatible. So here is an image of MRI when device is placed in the spinal cord for stimulation of the spinal cord. And it's effective in stimulation. So like I said, advantage of this small device is that you can actually deliver it via catheter or via an injection. So for emergency, for example, we believe it might have space when you're out of hospital, you can inject device very easily into the heart for stimulating in a critical situation. So here is a testing done at Rishi Arora's lab when he was still at Northwestern. Now he's at University of Chicago. We injected it inside the heart of the dog. And again, you can see on-demand pacing here done by our device. So we can also achieve multi-chamber pacing. So here is example we do by ventricular pacing when two different pacemakers are placed on left and right ventricle. Both pacemakers are controlled by light, but they are controlled by different wavelength of light. So we can independently control them, a different pacing paradigm. So you can see here a different part of the spectrum. They're completely independent. They do not have crosstalk. So we also think another potential application is for TAVR-TAVI patients. As you know, TAVR revolutionized aortic valve disease treatment, so replacing surgical treatment with implantation of this relatively easy implantation via catheter of TAVR-TAVI device. One of the problems of this therapy is that about 20% of patients develop AV block because this device, when it's implanted, is really close to the conduction system of the heart. And our device, pacemaker, can be integrated very easily onto this TAVR device. And as you can see, if it's placed properly against conduction system of the heart. In this case, we had six pacemakers placed on the heart, and you can see two of them were not aligned with the conduction system. They did not capture, and the others four are capturing quite nicely. So it's safe. So this is a safety data for inflammatory markers. You can see basically we don't have any evidence of inflammation. Body weight of animals is not altered, so everything is fine. And also, if you replace, so we have now zinc molybdenum configuration, different metals essentially. And you can see in this case, lifetime of the device is beyond two weeks, so we can basically build device for different duration of bioresorbable pacemaker. So let me conclude that I think that development of this transient electronic platform opens up new opportunities for temporary sensors, temporary actuators of various kinds. And I think first application which could be really developed is for children after cardiac open heart surgery like Walt Lillehei did in 1950s. So this would be interesting to develop in the next few years. And I would like to give credit to both teams of John Rogers, especially Yamin Zhang, who was the first author on the paper, and Eric Ritkin, who is co-author from my lab. So they really drove this project. And also, our paper was covered in many different places. This is the Times of London, so they actually did a really good job describing the mechanisms, how it works in very simple terms. Thank you, and I'll be happy to answer any questions. Thank you. That's a terrific, really great example of bionanomaterials interfacing into medicine. Please. A really fascinating talk. Quick question. There's something I missed. Why the optics? Meaning, couldn't you just have electronics to pace? I mean, I understand because of temporary pacing, but if you weren't thinking temporary, you were thinking more permanent and less bioresorbable. Could that be done without the optics? Yeah, it could be. But again, the question is the size of the device. So basically, if you want to do RF or some other means, it means you have to essentially increase capacity of your battery dramatically, and then you will have non-bioresorbable parameters. Ah, so I missed that. So the optics is not just timing, it's also providing, got it. Right. Although, no, but you still can implement fully bioresorbable if you have, for example, inductive power transfer. So then you can control electrically. The problem with that is why we went optically, because inductive power transfer requires certain size of your antenna. So when you charge your phone, you notice your magnetic base is pretty sizable. So unfortunately, it's pretty much a size of approximately a dime, not less. So if you want to make it smaller, you're stuck with this size. So only optical control allows it. And also, you have to remember that optical, infrared light propagates very nicely inside the human body. So you can very tightly control it at a short distance, and it's quite safe, of course. Yes. Yes. Igor, brilliant as always. Thank you. I was curious, you were just mentioning that. What's the depth that you can penetrate with the light? Can you do it from the skin onto the hard surface in a human situation? Yeah. Yeah. So we run basically several tests. So this is, of course, number one question, safety, how you can control. So we did light transport modeling of the human chest. So we can safely penetrate six, seven centimeters. And then we also ran studies in cadaver and also in actually large animals. So basically, in pig and dog. So we can definitely control six, seven centimeters with a very low intensity of light. We can increase intensity of light and penetrate also deeper if necessary. But it is wavelength dependent, of course. OK. Thank you. And what about conductive charging? Do you have any heat issues at all with the sensor? Yeah. We, of course, had those questions from reviewers. We also were very serious to address that. So basically, no, not really. These are millisecond long pulses. So they really don't increase temperature at all. And what about outside electronic influences affecting the sensors? So the good news was that wearable electronics has been already around for quite some time. And Roger's group developed several startups, about, I believe, six, seven startups, which makes various types of electronics. They already debugged it quite nicely. So essentially, there is really no problem at all with the temperature produced by wearable components. Thank you. Great. OK. So thank you very much. Thank you. Thank you. It's my pleasure to introduce our next speaker and my colleague, Dr. Jason Bradfield from UCLA, who will be speaking with us about renal denervation. Thank you all for sticking around for the last session. That's a tough act to follow. I'll provide some less impressive data, but maybe currently clinically relevant for arrhythmia management related to renal denervation. I'm going to talk a little bit about ways that we can treat arrhythmias that are not just based on substrate. As ablationists, we target substrate, but there are additional ways that we can modify arrhythmia substrates. And our group, as many of you may know, has a big interest in autonomic modulation or interventions to treat ventricular arrhythmias, and that's sort of how we got involved in this area. The AHA put out a nice scientific statement that kind of gives a good overview of really what this was developed for, which is treating hypertension, right? So there's been a number of studies with some mixed results, but generally positive, showing a modest reduction in blood pressure using a number of different catheters for renal denervation for hypertension. Specifically, there's the spiral radiofrequency catheter. There's a cryo-balloon catheter, as well as a catheter that can get into the interstitial space and deliver alcohol to affect the renal nerves. But the general consensus is that there's a modest reduction. If you look through all the studies that have been done, there's a single-digit improvement in systolic blood pressure, despite whichever group you're looking at, whether they have minimally treated hypertension, treated with a couple of medications, or even highly resistant medication. The results are relatively conserved throughout those groups. As arrhythmia physicians, we've been looking for ways to increase our success rates for certain ablations. We're great at ablating SVT with 90-plus success rates. When it comes to VT and it comes to AFib, those success rates are not quite as high. In the IVTCC, the VT success rate at one year was about 70%. We know that in our AFib population, that's probably closer to 80 in paroxysmals, less so in persistence. So how do we fill that gap? What things can we do to intervene for these patients? If we can't affect the substrate, can we affect the triggers and other drivers of arrhythmia? And in some arrhythmias, where perhaps we've considered them unablatable, although there is new data in these areas like ventricular fibrillation, can autonomic modulation be a standalone treatment perhaps? And that's how we really got into this area, working with cardiac sympathetic denervation as a treatment for ventricular arrhythmias, targeting the triggers of the ventricular arrhythmias in addition to the substrate if they are ablation candidates. Of course, this high sympathetic tone and low parasympathetic tone, this combination of features in heart failure patients often leads to a driver of arrhythmia. So we have scars and we have triggers, and combined we get ventricular tachycardia. So there are a number of ways we can intervene on the autonomic nervous system, both acute, subacute, and chronic. And a number of folks, including us, has looked at renal denervation as one of those more chronic interventions. And at least at our institution, it's become at least part of the algorithm, something to discuss as a treatment as we kind of move through the treatment of these patients as they prevent with BVT storm. And I'll show you some of that data from our group. It all really kind of goes back to the work from a number of people in our group, including Jeff Ardell, who we recently unfortunately lost, showing that if you intervene on the sympathetic nervous system in patients, this is a porcine model, but where you have coronary ischemia, you induce coronary ischemia, you can see this rapid rise in norepinephrine levels. And those ischemic subjects become more inducible from ventricular fibrillation. If you intervene at the level of the cardiac sympathetic denervation, much like a cellic ganglionectomy, you can still see a pretty high circulating norepinephrine level, but ventricular fibrillation inducibility goes down substantially. And that kind of is at the level of having a cardiac sympathetic denervation procedure by a surgeon. If you take that to the next level, which is to basically do something similar to a heart transplant, norepinephrine levels go down, but you actually don't see that much more of a decrease in ventricular fibrillation inducibility. So all the things that we're doing, including renal denervation, are to try to mimic some of these changes in terms of the sympathetic tone. So we started looking at ventricular renal denervation for ventricular arrhythmias. Others have looked at it for atrial fibrillation, and there have been a number of studies, some increased, some positive, some somewhat neutral. But the general idea is that when you have afferent cardiac sympathetic nerve transmission, it's associated with this increased renal nerve activity and norepinephrine spillover. So you see this 47% reduction in norepinephrine spillover with renal denervation, decrease in sympathetic nerve firing. And you also see some associated structural changes or improvements, if you will. Decrease in LA size, decrease in LV mass, decrease in LV fibrosis, likely in correlation with having a change in the renal angiotensin system or inhibition of that system. So in hypertensive patients that have never had AFib, there's been shown to be a decrease in asymptomatic AFib episodes with renal denervation for patients treated purely for hypertension. And at least in some studies, an incremental benefit of adding renal denervation to AFib ablation in terms of outcomes from Steinberg and colleagues, and a subsequent meta-analysis showing similar. We started looking at this for VT, and this was around 2013 or so, in a small combined cohort of patients with refractory ventricular tachycardia, showing at least a trend toward improvement. And a number of groups looked at this, and in this review, there were six studies. Again, taking systematic reviews with a little bit of a grain of salt, just because of the publication bias of positive studies, but notwithstanding, there was a trend towards improvement. We took it a little step further and said, okay, what about the highly resistant patients? These are all patients from our institution that failed ablation, then they were taken for cardiac sympathetic denervation and failed cardiac sympathetic denervation, and then they were taken for renal denervation. So probably the sickest of the sick. And remember, this was done with a standard ablation catheter, a standard endocardial ablation catheter, not a specifically designed catheter for renal denervation. In 10 patients, we did see a trend in improvement of ventricular arrhythmias, both ATP and ICD shocks. But when you really break that data down, the patients that had a response, or at least a partial response to cardiac sympathetic denervation, so they were able to leave the hospital, have their surgical procedure, went home, did okay for a little while, and then had more VT, came back and had successful renal denervation and did very well. Those were the staged patients. The patients that couldn't leave the hospital, that had minimal to no response to cardiac sympathetic denervation, all did poorly. So there was some predictive value of having response to autonomic interventions already that led to this breakdown in the data. Obviously there's a lot of unknowns in this field. What's the best catheter? I showed you there's a number of catheters in development. What's the true target? Can we get it from the venous system? That's something that my colleague, Dr. Arzola, who couldn't be here today, has worked on in his lab, which is targeting this aorticorenal ganglion instead of just this kind of broad ablation of the arteries, hoping to get at these nerves, but targeting the ganglia specifically. His group has looked at that and published in this area. It turns out that these ganglia are highly reproducible. They stain almost exclusively for sympathetic nerves and activity. They can be accessed from a venous route, which from a clinical standpoint has potential benefit in terms of complications. You can get a clear functional response from renal artery stimulation, I mean the ganglia stimulation versus renal artery. You see more norepinephrine and epinephrine release. You see larger changes in ARI. And like I said, you can attack this from a venous access site. I'll skip a couple in a matter of time. When you take a porcine model and you break them up into ganglion ablation, artery ablation, or sham ablation, and then induce ischemia and try to induce VT or VF, you see a clear difference in the outcomes in this animal model, which is the time to induction of VT, the frequency of PVCs, and the VF survival of the pigs that had ganglion ablation was significantly different than those that had standard renal artery denervation. And then the next question is, if it can be addressed from the venous system in pigs, does that necessarily translate to humans? And at least from cadaveric data that they have, those ganglia stain very similarly in terms of the sympathetic activity, and they are reproducible anatomically, which is important for any future procedural decision making. So in conclusion, we've done a lot of work with autonomic modulation, in particular CSD, and CSD patients have about a 50% one-year VT freedom, though the majority of the patients have a decrease in their burden. Renal denervation has some potential to potentially be an adjunctive therapy for both atrial and ventricular arrhythmias. I don't see it as a standalone therapy, but as the techniques and technologies improve, it is possible that adding these to other standard therapies may increase our success rate. And we just need more science to really understand what's the true targets. Is it the aortical renal ganglion? Is there other mechanisms and ways to do this safely and translate that to human work? Thank you very much. Thank you, Jason. The floor is now open for any questions. Can I ask a question while someone else comes up? Do you think, like, one of the problems with the renal denervation study for hypertension was A, to know where you actually had denervated or not, and you wouldn't really know that until you got post-mortem material, so were there false negatives? And the other thing, were they neurogenically hypertensive, which you would think you would get maximum benefit from? So I guess my question to you for the cardiac patients, are you stratifying them based on high sympathetic phenotyping profile? Do they get the best bang for the intervention? Yeah, it's a great question. The majority, almost all of the cardiomyopathy patients are not hypertensive, right, because either they have a very low EF and on multiple medications, and so at least at baseline, they're not hypertensive on the ventricular side. A lot of the AFib patients are, but on the ventricular side, I don't think that is true. Now, to your point, when it comes to sympathectomy as a surgical procedure, we have tried to correlate patients' response in the ICU if they get a percutaneous procedure on the and the response to that as a predictor of the response to the surgical procedure. Same sort of question that you're asking, and the answer is we haven't really been able to see that correlation. Now, maybe that's a numbers game, but to go back to your other point is we had a really hard time when we were doing this in the early stages of assessing response, because a lot of these patients weren't under general anesthesia. They had pain. They had other things that would affect their blood pressure and things that we were trying to measure, and we ultimately couldn't consistently target it. There's time for one question. Yeah. Jason, very nice presentation. I just want to ask that question about pain. I remember when we were playing with this very early, trying to do high-frequency stimulation, I could never figure out if it was just a pain response or if it was something specific. Is there a way to? These guys would probably know better than me, quite frankly, but we basically abandoned high-frequency stimulation. We did it for a while because we wanted to be scientific, and then we just felt like we had no idea how to interpret any of the data. Again, any procedure where you're, until this becomes more targeted, any procedure where you're just empirically ablating an artery in hopes of getting to some nerves on the outside is going to be fraught with, did you even have the effect? But I think that's true of many of these autonomic interventions. When we do percutaneous stellate blocks, the question is, did they even hit the right thing? And how do you target that, and how do you know? Given that, so you'd shown some data where patients that are sort of end-stage are using renal denervation as last resort didn't do as well, so it seems, is it that it's, you see that it's difficult to incorporate this earlier in the treatment algorithm at this point without a better assessment or a way to risk stratify? Yeah, I mean, I think somebody, if we believe that it's potentially beneficial, there has to be a bigger study with early intervention. We've obviously used this as a very end-stage intervention, and some of them did, all those patients were very sick, so the ones that did well with it still had bad chromopathy, what have you, but there was something different about the patients that couldn't get out of the hospital, right? It's much like radiation treatment. Our patients haven't done very well. Are they so sick that we just are waiting too long, or is that just the technology isn't really what it is? But, so yeah, I think it needs to be done in an earlier stage, and in VT, that's harder because Vivek doesn't get a referral for their first ATP. He gets them when they storm and have to be transferred, right? Same with us, right? So it's a little bit challenging. Great. Thank you, Jason. So our final presenter, Dr. Peter Hanna from UCLA, is going to be talking about cervical vagal stimulation. Great. All right, I'd like to thank the organizers for the opportunity to speak with you today about cervical vagal nerve stimulation. So to understand the approach to cervical VNS, we'll first talk about the role of the parasympathetic nervous system in arrhythmogenesis, the effects of cervical VNS on arrhythmias, and strategies to perform VNS. First we need to, I'd like to set the groundwork for the actual cardiac neuroaxis before we dive in. So the cardiac autonomic nervous system is made up of the sympathetic and parasympathetic limbs and consists of complex interacting feedback loops between the two limbs. So starting at the level of the heart, we have the intrinsic cardiac nervous system where the mechanical and electrical activity is sensed, locally processed, and then there's efferent or motor output to the heart as part of cardiocardiac reflexes. At the next stage up, we have sensory information that's processed at either the stellate ganglia or dorsal root ganglia with efferent output, again, through the sympathetic nerves via the stellate ganglia, and these make up the intrathoracic and spinal reflexes, respectively. And then where we'll focus most of our attention today is looking at the vagus nerve, where afferent information processed by the nodus ganglion is processed at the level of the brainstem and then efferent output through that vagus nerve. And as you can see, there are higher order cortical centers that also interact with these different reflexes. And between the different loops, there's also crosstalk. So you can quickly see how this becomes a complicated system where stimulating the vagus, for example, may interact with the sympathetic nervous system and vice versa, and where even as you're stimulating the vagus nerve, not only are you affecting the motor output down to the heart, but also afferent information going back up to the brain. So in a canine model, Natal actually had shown that with multi-electrode arrays on the atria, with vagal nerve stimulation and sympathetic nerve stimulation, when that was done to the point that ERP was reduced to similar levels, and the wavelength of reentry was also reduced to similar levels, it was actually the vagal nerve stimulation that increased AF duration more so. And it was attributed to spatial dispersion of atrial ERP, which is shown here in the bottom right with the standard deviation of ERP. So that heterogeneity was thought to explain the concept of vagal AF. In addition to stimulating the vagus nerve, we can also look at neural activity. And Tan et al. actually, in a canine model, were able to perform atrial pacing for periods of a week, followed by a day of monitoring in their AFib model. And this was repeated until sustained AFib was achieved, and this took about three weeks. During that time, the left stellate and vagal nerves were activity, and those nerves were recorded. And episodes of paroxysmal AFib were identified prior to that three-week mark at which the sustained AFib was induced. And it was noted that bursts of left stellate and vagal nerve activity, as you can see here with the spikes of vagal nerve activity and stellate ganglion neural activity preceded the episode of paroxysmal AFib. They went a step further, and in a group of animals actually performed cryoablation of the left stellate, as well as the superior cardiac branch of the left vagus. And then they recorded activity upstream of where they had ablated. And as you can see here, despite having the bursts of activity, these dogs were no longer exhibiting any atrial fibrillation or atrial arrhythmias. So from this work, there's been more of an understanding of the role of the autonomic nervous system in AFib. And this is a figure that's now in the guidelines that were published in 23, where you can see that autonomic triggers for AFib are associated with increased adrenergic and cholinergic nerve activity, and that with the natural history of atrial fibrillation as it moves towards persistent and more permanent forms of atrial fibrillation, it's characterized by the autonomic remodeling. And from that, the concept of AF begets AF. So what I've shown so far is how vagal nerve stimulation actually causes atrial fibrillation, but how does it actually limit, or how can it be used to treat AFib? So in this experiment, in a canine model, a neurostimulator was implanted at the left vagus. And after one week of low-level vagal nerve stimulation, it was noted that there was reduced left stellate ganglion neural activity. And when they actually quantified active versus sham limbs of the experiment, there was less paroxysmal AFib or paroxysmal atrial tachyarrhythmias that was noted. Li et al. also showed that actually, the longer that you stimulate, there's even less AFib inducibility. So with catheters in the pulmonary veins, again, in the canine model, as well as at the atrial appendages, the longer that the low-level vagal nerve stimulation was applied, from one to three hours, there was an increase in the threshold at which the high-frequency stimulation at these six different sites actually induced atrial fibrillation. Now, this has all been in dog model. This has also been taken to humans, where Dr. Stavrakis's group has shown with low-level vagal nerve stimulation at the level of the SVC by actually stimulating the pre-ganglionic fibers that are running at the lateral aspect of the SVC at time of cardiac surgery. And if that stimulation is performed for the 72 hours thereafter, there's less risk of post-operative AFib over the subsequent 20 days. They also took blood samples immediately post-operatively, as well as at the 24 hours and 72 hours, and showed that there was a decrease in inflammatory cytokines, TNF-alpha and IL-6, suggesting that there was also an anti-inflammatory effect through the cholinergic anti-inflammatory pathway to exert its effect. So everything I've talked to you about now has been regarding atrial fibrillation, and when we think about VT, we usually think of cardiac sympathetic denervation as taking away that sympathetic excitation. But I wanted to show this example from the 70s of four patients in whom edrophonium and acetylcholinesterase inhibitor was administered, followed by carotid sinus massage. Usually we think of this for treating SVT, but in these patients, this was actually used to abort their VT, suggesting that increased vagal nerve stimulation may be helpful in these patients. And so in our group, we've looked at a post-MI model in pigs, and how chronic VNS can be beneficial. And so in pigs, we've actually implanted VNS devices, titrated therapy, and then induced an MI, and then 68 weeks later, these pigs have undergone an EP study to look at inducibility. So as you can see here, we've gone through an S1, S2, S3 protocol, you can see with induction of VT in an animal with MI. Conversely, in an animal that had chronic VNS, even going out to S4, we weren't able to induce. And this is quantified here, where there was really reductions in inducibility. And of note, if you see here the comment VNS off versus VNS on, that's really to signify that it didn't matter if the stimulator was actually on at the time of the inducibility study, that it was really the six to eight weeks plus of stimulation had already exerted its benefit, presumably through some remodeling and essentially neural memory. The late Professor Ardell had actually written extensively about a concept called the neural fulcrum. Essentially, VNS has been looked at in a lot of the heart failure trials and had mixed to largely negative results, namely the CardioFit Innovate HF and Nectar HF trials. And in this stimulus response curve here, as you can see, it's frequency, amplitude, and change in heart rate. The thought is that using stimulation parameters that exerted an effect on heart rate was actually not beneficial, that the therapeutic target zone should be with a null heart rate response. So again, signifying that low-level vagal nerve stimulation. And that was what was actually conducted in the Anthem HF trial, which did actually show an improved benefit with the six-minute walk test. In addition to how you stimulate, where you stimulate is important. So as I mentioned, there's afferent and efferent flow through the vagus nerve. So just putting it on a cuff electrode and stimulating it, it's a little bit difficult to actually assess the response. And so understanding the neuroanatomy may actually help us be more selective in how we stimulate the vagus nerve. So our group collaborated with the University College London with Dr. Holder's lab there, to actually show how we, to really characterize the vagus nerve. To do that, the different stimulations were performed on the vagus nerve before and after vagotomies. And physiological readouts, whether EKG, left ventricular pressure, EMG, at the level of the laryngeal muscle, looking at respirations, could be performed. And through selective stimulation, using a cuff electrode with 32 electrodes, you could then sort of tease apart the functional organization of the vagus nerve. And again, by severing the vagus, you can then look at afferent versus efferent outflow towards the heart. At the end of the experiment, the animals were sacrificed. The vagus nerve was then studied ex vivo with micro-CT. And as you can see here, different fascicles of the nerve could then be identified, those that were specific either for pulmonary, recurrent laryngeal, cardiac, or mixed. And what they actually found is that the afferent and efferent limbs for the cardiac projections were actually on distinct parts of the vagus nerve, suggesting that you could then come up with a way to selectively stimulate either the afferent or the efferents from the heart. This has now been extended to the humans. So in this example, in the Macefield group have actually looked at microneural recordings from the vagus. And so they actually stuck needles into the left vagus nerve, and then measured respiration, blood pressure, heart rate. And what they show in this representative image is at baseline, this neuron is actually silent. But with slow deep breathing, you can actually see with the R-wave frequency as the heart rate slowed. Particularly during expiration, this neuron was actually firing, suggesting that was specific to that part of the cardiorespiratory cycle. So to conclude, vagal nerve stimulation may be used to treat atrial and ventricular arrhythmias. The vagal nerve activity increases prior to episodes of atrial fibrillation, along with the sympathetic neural activity. That low-level VNS has both anti-adrenergic and anti-inflammatory effects, and can be used to reduce the burden of atrial and ventricular arrhythmias. But we really need to understand the vagal neuroanatomy more so to really improve on the technique of cardiac neuromodulation. And with that, I have many people to thank, both at UCLA as well as our collaborators at other sites, and our funding, and as well to you for staying for the last talk of the session. So, thank you. Thank you. Yeah, great talk, really enjoyed that. So in the slide that you showed with the structure of the vagus nerve, how much variability did you see? So that was in an animal model, right? That's right. Yeah, in the pic. So how much variability did you see there from animal to animal? And then kind of projecting that forward, how much do you think there's going to be in the human? Because I think that's really, we've talked a lot about different variability from patient to patient for autonomic stimulation. So I'd be interested in your thoughts on that. As you can imagine, it is quite a challenging protocol to do. So there were 10 animals within the functional limb, and then five animals that were studied ex vivo. So understanding that there is a limited sample size, at least for the cardiac aspect of it, it did seem consistent in terms of afferents and efferents being on lateral aspects of the vagus nerve. So that did seem to be a consistent finding. Thanks, Peter. Hey, Peter, excellent talk. I was wondering, I was surprised when you said that in your animal model of infarct, you couldn't get it to go into VT. I was expecting you were to say there was less VT. But could you speak a little bit, like for the infarction, what about size were you going about for the infarction? And what was the extent of the infarcted tissue? How severe was the model? Yeah, so our infarcts were actually quite consistent between animals. And if anything, with vagal nerve stimulation, what I didn't mention is that it does seem to consolidate the scars. So as opposed to a more patchy border zone, we actually saw a more dense scar that maybe had conferred some of that benefit in terms of the inducibility. But it did seem that with VNS, it was protective in that we weren't able to induce VT as much. There was one animal in which it was inducible. I guess to follow up, like what extent of the myocardium, I assume it was the LAD? Oh, yes. Or what extent of the myocardium was affected? We inject microspheres distal to the second diag for the LAD. OK, thank you. Carolyn Remmer, Amsterdam. I was wondering, you mentioned that you don't need the acute effects, but the chronic remodeling is sufficient. So what exactly happens to the innervation during all of this in the heart? Have you looked at that? Yes, so regarding that, there has been an increase of glia actually that have been noted in relation to the innervation. But it didn't seem to affect the traditional sympathetic hyperinnervation that is typically characterized around the level of the scar. But it's still an area of interest to look at actually what the structural changes that go along with this. And also heterogeneity in innervation might be very relevant. Yeah. Thank you. Maybe just one question for me, Peter. The vagus sort of paradoxically is interesting, isn't it? Because on one hand, it's nature's calcium channel blocker for high sympathetic drive. But you intimated that you've got some occurrence of dual autonomic activation. And that happens very rarely in life, like REM sleep and just after exercise. So are those two time points when you do get dual, double autonomic activation, is there evidence that that becomes a trigger event for AF? Do we know that? Past the animal model, that shows that, again, with direct recordings and left vagus, left stellate, there were the bursts of activity that were shown prior to AFib. So that's the extent of, I think, what's been shown. Yeah. I think you can demonstrate it experimentally. I just wanted the clinical phenotype with Holter recordings and things like that. I would say it's typically dichotomized into vagal versus sympathetic, right? So either, for example, and typically, it's thought to have a diurnal variation in patients that have their AFib episodes. Those that wake up at 3 AM with AFib presumably are vagal versus those that have it during their daytime hours. Yeah, so REM sleep time. Yeah, OK, please. Yeah, great talk. So I just have a quick question. Back to the pig VT model, I wonder, did you check any ion channels or parents? Or did you sequencing and say any changes of gene between groups? We have banked tissue for sequencing, but didn't do any of the cellular EP work. OK, so thank you very much, Peter. And I'd just like to thank all the speakers for great talks, and especially you, the audience, for hanging in there for the last session. Maybe when we're in Chicago next year, we'll try and push this a little bit further up the program, if we can talk to the programming committee. But hopefully, you would have seen where technology is now starting to meet the biology and the clinical utility that could translate from this going forward. So I think what you're seeing is really early days. And then in 5 to 10 years time, I think you'll probably find that these sessions will be packed out because of that clinical utility and translation. So hang in there. This is really early days. And have a safe trip back home, wherever you're going. Thank you.

cardiovascular interventions

neurological interventions

baro-stimulation therapy

biodegradable electronics

bioresorbable pacemaker

renal denervation

autonomic modulation

vagal nerve stimulation

arrhythmia management

therapeutic interventions